NR4A Receptors in Alzheimer's disease

阿尔茨海默病中的 NR4A 受体

• 批准号: 8593735
• 负责人: Rebecca R Skerrett
• 金额: $ 4.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593735
• 关键词: APP-PS1; Address; Affect; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid beta-Protein; Animals; Astrocytes; Automobile Driving; Bexarotene; Brain; Cessation of life; Characteristics; Clinical; Cognition; Complex; Dementia; Development; Diffuse; Dopaminergic Cell; Elderly; Exhibits; Family; Family member; Functional disorder; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Inflammation; Inflammatory; Lead; Ligands; Longevity; Maintenance; Memory; Memory Loss; Microglia; Modeling; Mus; NR4A1 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Receptors; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Persons; Play; Positioning Attribute; Production; Protein Isoforms; Proteins; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research; Retinoids; Role; Route; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Staging; Stimulus; Symptoms; Synapses; Testing; Therapeutic; Time; Work; amyloid pathology; behavioral impairment; cell type; dopaminergic neuron; effective therapy; experience; mouse model; mutant; neuroinflammation; neuron loss; neuronal survival; neuroprotection; new therapeutic target; overexpression; presenilin; prevent; public health relevance; receptor; receptor expression; response; tau Proteins; therapeutic target

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly and affects millions of people worldwide. AD pathology includes characteristic amyloid plaques and neurofibrillary tangles composed of tau and at later stages synaptic loss and significant neurodegeneration. Major symptoms of AD, including memory loss and cognitive decline, correlate closely in their severity to the degree of neuronal loss an individual experiences. Previous work from our lab and others has proposed that nuclear receptors are important players in the clearance of amyloid pathology and inflammation in AD mouse models, but the role of NRs in neurodegeneration has not yet been addressed. The NR4A subfamily of NRs are known to have neuroprotective effects, and dysregulation of NR4A family members Nurr1 (NR4A2) and Nur77 (NR4A1) is implicated in Parkinson's disease and other neurodegenerative disorders. The hypothesis driving this proposal is that NR4A dysregulation is a key component of neurodegeneration in AD and that decreasing NR4A expression will have a direct impact on neuronal survival. One specific goal of this proposal is to determine if NR4A expression changes with pathological progression in a mouse model of AD. This problem will be addressed using the 5XFAD, a mouse model of AD that exhibits significant neuronal loss, especially in the hippocampus and layers V/VI of the cortex. Animals will be assessed for overall NR4A expression at different stages of neurodegeneration, and cell- type specific levels of NR4As in neurons, microglia, and astrocytes will be evaluated to determine contributing cell types. A second specific goal of this proposal is to determine if the deletion of NR4A receptors exacerbates neuronal death in an AD model. 5XFAD mice will be crossed to mice conditionally null for Nurr1 and assessed for changes in severity and time of onset of neuronal death. NR4A expression will also be stimulated in the 5XFAD mouse using pharmacological agents such as the RXR agonist bexarotene to determine if NR4As provide a potential therapeutic target for treating AD-related neurodegeneration. Characterizing the role of NR4A family NRs in AD will allow for a better understanding of the mechanisms of neuronal loss, and could provide a novel target for therapeutic treatment of AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）是老年人痴呆症的最常见原因，影响着全世界数百万人。 AD 病理学包括特征性淀粉样斑块和由 tau 蛋白组成的神经原纤维缠结，以及后期的突触丧失和显着的神经变性。 AD 的主要症状，包括记忆丧失和认知能力下降，其严重程度与个人经历的神经元损失程度密切相关。我们实验室和其他人之前的工作提出，核受体在 AD 小鼠模型中淀粉样蛋白病理和炎症的清除中发挥着重要作用，但 NR 在神经退行性变中的作用尚未得到解决。 NR 的 NR4A 亚家族已知具有神经保护作用，NR4A 家族成员 Nurr1 (NR4A2) 和 Nur77 (NR4A1) 的失调与帕金森病和其他神经退行性疾病有关。推动这一提议的假设是，NR4A 失调是 AD 神经变性的关键组成部分，减少 NR4A 表达将对神经元存活产生直接影响。 该提案的一个具体目标是确定 NR4A 表达是否随着 AD 小鼠模型的病理进展而变化。这个问题将通过 5XFAD 得到解决，5XFAD 是一种 AD 小鼠模型，表现出显着的神经元损失，特别是在海马体和皮层的 V/VI 层。将评估动物在神经变性的不同阶段的整体 NR4A 表达，并将评估神经元、小胶质细胞和星形胶质细胞中 NR4A 的细胞类型特异性水平，以确定起作用的细胞类型。该提案的第二个具体目标是确定 NR4A 受体的缺失是否会加剧 AD 模型中的神经元死亡。将 5XFAD 小鼠与 Nurr1 条件性无效的小鼠杂交，并评估神经元死亡的严重程度和发生时间的变化。还将使用 RXR 激动剂贝沙罗汀等药物刺激 5XFAD 小鼠中的 NR4A 表达，以确定 NR4A 是否为治疗 AD 相关神经变性提供潜在的治疗靶点。表征 NR4A 家族 NR 在 AD 中的作用将有助于更好地了解神经元损失的机制，并可能为 AD 的治疗提供新的靶点。